Cell proliferation following injury to alveolar epithelial cells is necessary for repair, but chronic proliferation may result in the development of diseases such as pulmonary fibrosis and lung cancer. Hypothesis #1 is that activation of the c-Jun NH2-terminal Kinase (JNK) cascades will be critical to the development of cellular proliferation by asbestos and particulate matter (PM) in vitro. A second hypothesis is that JNK activation and cell proliferation play a role in epithelial cell repair, and may alter the development of pulmonary fibrosis. The patterns and kinetics of JNK activation will be correlated over time with the development of cell proliferation by agents selectively inducing these phenotypic endpoints in mouse alveolar type II epithelial (C10) cells (Specific Aim #1). To determine whether activation of JNK is causally related to the development of cell proliferation, transfection of C10 cells with a dominant negative construct of JNKI will be used to determine if asbestos or PM-induced cell proliferation is significantly ameliorated (Specific Aim #2). To test Hypothesis #2, transgenic mice over-expressing the dominant negative JNK1 construct will be generated using the alveolar epithelial cell-specific human surfactant protein C promoter. Transgenic mice will be exposed to asbestos by inhalation and characterized, using quantitative markers for cell proliferation and pulmonary fibrosis, to determine if the severity and extent of disease are altered (Specific Aim #3). Results will indicate not only whether alveolar type II epithelial cell proliferation is a mechanism of repair in pulmonary fibrosis, but may provide a rationale for modification of cell signaling pathways governing cell proliferation in the treatment of fibrotic lung disease.